Does enhanced respiratory–sympathetic coupling contribute to peripheral neural mechanisms of angiotensin II–salt hypertension?

Abstract

Hypertension caused by chronic infusion of angiotensin II (Ang II) in experimental animals is likely to be mediated, at least in part, by an elevation of ongoing sympathetic nerve activity (SNA). However, the contribution of SNA relative to non-neural mechanisms in mediating Ang II- induced hypertension is an area of intense debate and remains unresolved. We hypothesize that sympathoexcitatory actions of Ang II are directly related to the level of dietary salt intake. To test this hypothesis, chronically instrumented rats were placed on a 0.1 (low), 0.4 (normal) or 2.0% NaCl diet (high) and, following a control period, administered Ang II (150 ng kg −1 min −1 , s.c.) for 10–14 days. The hypertensive response to Ang II was greatest in rats on the high-salt diet (Ang II–salt hypertension), which was associated with increased ‘whole body’ sympathetic activity as measured by noradrenaline spillover and ganglionic blockade. Indirect and direct measures of organ-specific SNA revealed a distinct ‘sympathetic signature’ in Ang II–salt rats characterized by increased SNA to the splanchnic vascular bed, transiently reduced renal SNA and no change in SNA to the hindlimbs. Electrophysiological experiments indicate that increased sympathetic outflow in Ang II–salt rats is unlikely to involve activation of rostral ventrolateral medulla (RVLM) vasomotor neurons with barosensitive cardiac rhythmic discharge. Instead, another set of RVLM neurons that discharge in discrete bursts have exaggerated spontaneous activity in rats with Ang II–salt hypertension. Although their discharge is not cardiac rhythmic at resting levels of arterial pressure, it nevertheless appears to be barosensitive. Therefore, these burst-firing RVLM neurons presumably serve a vasomotor function, consistent with their having axonal projections to the spinal cord. Bursting discharge of these neurons is respiratory rhythmic and driven by the respiratory network. Given that splanchnic SNA is strongly coupled to respiration, we hypothesize that enhanced central respiratory–vasomotor neuron coupling in the RVLM could be an important mechanism that contributes to exaggerated splanchnic sympathetic outflow in Ang II–salt hypertension. This hypothesis remains to be tested directly in future investigations.